Several human pathogens express structurally divergent forms of lipid A, the biologically active moiety of LPS, as a strategy to evade innate immune detection and establish chronic infection. The oral mucosal pathogen Porphyromonas gingivalis intrinsically expresses underacylated lipid A moieties and can modify the phosphorylation of lipid A, leading to altered TLR4 signaling. In addition to local immunopathology, significant clinical and experimental evidence implicate P. gingivalis as risk factor for the development of chronic systemic inflammatory diseases including rheumatoid arthritis, cancer, and cardiovascular disease. Dysregulated T cell responses are believed to play a role in these inflammatory disorders. While the role of lipid A modifications in evasion of innate immune signaling is established, how this influences adaptive immune responses that contribute to dysregulation of host immunity has not been explored. Myeloid dendritic cells (DCs) and their blood monocyte precursors play an important role in bridging the innate and adaptive arms of the immune system during Gram-negative bacterial infection. TLR4 activation in these cells induces a distinct maturation phenotype that promotes their mobilization to immune T cell areas for initiation of antigen-specific immunity. Despite the wealth of studies on P. gingivalis pathogenesis in the oral cavity, the immunological mechanisms underlying P. gingivalis mediated systemic inflammation are not well defined. We propose in this application to define the impact of P. gingivalis lipid A moieties on DC responses and T cell activation that contribute to P. gingivalis mediated systemic immunopathology. We hypothesize that the different lipid A species expressed by P. gingivalis drive DC responses leading to distinct T cell activation pathways that contribute to P. gingivalis-mediated systemic inflammatory outcomes. The following Aims are proposed to test this hypothesis: Aim 1. To define the role of P. gingivalis lipid A species and TLR4 signaling in DC responses and T cell activation in vitro. Aim 2.To define the role of P. gingivalis lipid A species on TLR4- dependent DC and T cell responses following P. gingivalis oral infection. Aim 3. To define the role of P. gingivalis distinct lipid A species and DC-specific TLR4 signaling in the development of P. gingivalis induced immunopathology in vivo. Strikingly, several Gram-negative bacteria that express immune-evasive lipid A are associated with increased risk of autoimmune disease, atherosclerosis, and cancer. Thus, these studies have broad implications and will provide important insights into the mechanisms by which Gram-negative pathogens alter systemic adaptive immune responses resulting immunopathology. !